Abstract
Skeletal dysplasias are a common, genetically heterogeneous cause of short stature that can result from disruptions in many cellular processes. We report the identification of the lesion responsible for skeletal dysplasia and male infertility in the spontaneous, recessive mouse mutant chagun. We determined that Poc1a, encoding protein of the centriole 1a, is disrupted by the insertion of a processed Cenpw cDNA, which is flanked by target site duplications, suggestive of a LINE-1 retrotransposon-mediated event. Mutant fibroblasts have impaired cilia formation and multipolar spindles. Male infertility is caused by defective spermatogenesis early in meiosis and progressive germ cell loss. Spermatogonial stem cell transplantation studies revealed that Poc1a is essential for normal function of both Sertoli cells and germ cells. The proliferative zone of the growth plate is small and disorganized because chondrocytes fail to re-align after cell division and undergo increased apoptosis. Poc1a and several other genes associated with centrosome function can affect the skeleton and lead to skeletal dysplasias and primordial dwarfisms. This mouse mutant reveals how centrosome dysfunction contributes to defects in skeletal growth and male infertility.
Highlights
Normal adult stature in humans is achieved primarily through regulation of long bone growth, which occurs through endochondral ossification [1,2]
We discovered that the spontaneous, dwarf mouse mutant chagun is PLOS Genetics | DOI:10.1371/journal.pgen
Mutation in Poc1a Causes Dwarfism and Male Infertility had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Summary
Normal adult stature in humans is achieved primarily through regulation of long bone growth, which occurs through endochondral ossification [1,2] This process begins with the differentiation of mesenchymal stem cells into chondrocytes in regions of the body where skeletal elements will eventually reside. Tight control of chondrocyte proliferation and terminal hypertrophic differentiation allows new bone tissue to replace terminally differentiated chondrocytes in a spatially and temporally regulated manner, ensuring the proper growth of the skeletal elements and the individual overall. Disruption of these processes can lead to skeletal dysplasias
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